Human Genetics of Diabetic Retinopathy: Current Perspectives

Diabetic retinopathy (DR) is a most severe microvascular complication which, if left unchecked, can be sight-threatening. With the global prevalence of diabetes being relentlessly projected to rise to 438 million subjects by 2030, DR will undoubtedly pose a major public health concern. Efforts to unravel the human genetics of DR have been undertaken using the candidate gene and linkage approaches, while GWAS efforts are still lacking. Aside from evidence for a few genes including aldose reductase and vascular endothelial growth factor, the genetics of DR remain poorly elucidated. Nevertheless, the promise of impactful scientific discoveries may be realized if concerted and collaborative efforts are mounted to identify the genes for DR. Harnessing new genetic technologies and resources such as the upcoming 1000 Genomes Project will help advance this field of research, and potentially lead to a rich harvest of insights into the biological mechanisms underlying this debilitating complication

Search for Heavy Leptons at Hadron Colliders

Four models are considered which contain heavy leptons beyond the three families of the standard model. Two are fourth-generation extensions of the standard model in which the right-handed heavy leptons are either isosinglets or in an isodoublet; the other two are motivated by the aspon model of CP violation. In all these models, the heavy neutrino can either be heavier than, or comparable in mass to, the charged lepton leading to the possibility that the charged lepton is very long-lived. Production cross section and signatures for the heavy leptons are computed for the SSC and LHC.Comment: 17 pages(8 figures are not included),TRI-PP-92-9

The 331 model with right-handed neutrinos

We explore some more consequences of the $SU(3)_L\otimes U(1)_N$ electroweak model with right-handed neutrinos. By introducing the $Z - Z'$ mixing angle $\phi$, the {\it exact} physical eigenstates for neutral gauge bosons are obtained. Because of the mixing, there is a modification to the $Z^1$ coupling proportional to $\sin\phi$. The data from the $Z$-decay allows us to fix the limit for $\phi$ as $-0.0021 \leq \phi \leq 0.000132$. >From the neutrino neutral current scatterings, we estimate a bound for the new neutral gauge boson $Z^2$ mass in the range 300 GeV, and from symmetry-breaking hierarchy a bound for the new charged and neutral (non-Hermitian) gauge bosons $Y^{\pm}, X^o$ are obtained.Comment: Slight changes in section 5, Latex, 16 page

Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer

The underpinnings of STAT3 hyperphosphorylation resulting in enhanced signaling and cancer progression are incompletely understood. Loss-of-function mutations of enzymes that dephosphorylate STAT3, such as receptor protein tyrosine phosphatases, which are encoded by the PTPR gene family, represent a plausible mechanism of STAT3 hyperactivation. We analyzed whole exome sequencing (n = 374) and reverse-phase protein array data (n = 212) from head and neck squamous cell carcinomas (HNSCCs). PTPR mutations are most common and are associated with significantly increased phospho-STAT3 expression in HNSCC tumors. Expression of receptor-like protein tyrosine phosphatase T (PTPRT) mutant proteins induces STAT3 phosphorylation and cell survival, consistent with a “driver” phenotype. Computational modeling reveals functional consequences of PTPRT mutations on phospho-tyrosine–substrate interactions. A high mutation rate (30%) of PTPRs was found in HNSCC and 14 other solid tumors, suggesting that PTPR alterations, in particular PTPRT mutations, may define a subset of patients where STAT3 pathway inhibitors hold particular promise as effective therapeutic agents.Fil: Lui, Vivian Wai Yan. University of Pittsburgh; Estados UnidosFil: Peyser, Noah D.. University of Pittsburgh; Estados UnidosFil: Ng, Patrick Kwok-Shing. University Of Texas Md Anderson Cancer Center;Fil: Hritz, Jozef. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos. Masaryk University; República ChecaFil: Zeng, Yan. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Lu, Yiling. University Of Texas Md Anderson Cancer Center;Fil: Li, Hua. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Wang, Lin. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Gilbert, Breean R.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: General, Ignacio. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Bahar, Ivet. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Ju, Zhenlin. University Of Texas Md Anderson Cancer Center;Fil: Wang, Zhenghe. Case Western Reserve University; Estados UnidosFil: Pendleton, Kelsey P.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Xiao, Xiao. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Du, Yu. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Vries, John K.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Hammerman, Peter S.. Harvard Medical School; Estados UnidosFil: Garraway, Levi A.. Harvard Medical School; Estados UnidosFil: Mills, Gordon B.. University Of Texas Md Anderson Cancer Center;Fil: Johnson, Daniel E.. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Grandis, Jennifer R.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unido

All-sky convolution for polarimetry experiments

We discuss all-sky convolution of the instrument beam with the sky signal in polarimetry experiments, such as the Planck mission which will map the temperature anisotropy and polarization of the cosmic microwave background (CMB). To account properly for stray light (from e.g. the galaxy, sun, and planets) in the far side-lobes of such an experiment, it is necessary to perform the beam convolution over the full sky. We discuss this process in multipole space for an arbitrary beam response, fully including the effects of beam asymmetry and cross-polarization. The form of the convolution in multipole space is such that the Wandelt-Gorski fast technique for all-sky convolution of scalar signals (e.g. temperature) can be applied with little modification. We further show that for the special case of a pure co-polarized, axisymmetric beam the effect of the convolution can be described by spin-weighted window functions. In the limits of a small angle beam and large Legendre multipoles, the spin-weight 2 window function for the linear polarization reduces to the usual scalar window function used in previous analyses of beam effects in CMB polarimetry experiments. While we focus on the example of polarimetry experiments in the context of CMB studies, we emphasise that the formalism we develop is applicable to anisotropic filtering of arbitrary tensor fields on the sphere.Comment: 8 pages, 1 figure; Minor changes to match version accepted by Phys. Rev.

A sex-specific role for androgens in angiogenesis

Mounting evidence suggests that in men, serum levels of testosterone are negatively correlated to cardiovascular and all-cause mortality. We studied the role of androgens in angiogenesis, a process critical in cardiovascular repair/regeneration, in males and females. Androgen exposure augmented key angiogenic events in vitro. Strikingly, this occurred in male but not female endothelial cells (ECs). Androgen receptor (AR) antagonism or gene knockdown abrogated these effects in male ECs. Overexpression of AR in female ECs conferred androgen sensitivity with respect to angiogenesis. In vivo, castration dramatically reduced neovascularization of Matrigel plugs. Androgen treatment fully reversed this effect in male mice but had no effect in female mice. Furthermore, orchidectomy impaired blood-flow recovery from hindlimb ischemia, a finding rescued by androgen treatment. Our findings suggest that endogenous androgens modulate angiogenesis in a sex-dependent manner, with implications for the role of androgen replacement in men

Towards the prediction of antimicrobial efficacy for hydrogen bonded, self-associating amphiphiles

Herein, we report 50 structurally related supramolecular self-associating amphiphilic (SSA) salts and related compounds. These SSAs are shown to act as antimicrobial agents, active against model Gram-positive (Methicillin-Resistant Staphylococcus aureus) and/or Gram-negative (Escherichia coli) bacteria of clinical interest. Through a combination of solution state, gas phase, solid state and in silico measurements we determine 14 different physicochemical parameters for each of these 50 structurally related compounds. These parameter sets are then used to identify molecular structure – physicochemical property – antimicrobial activity relationships for our model Gram-negative and Gram-positive bacteria, while simultaneously providing insight towards the elucidation of SSA mode of antimicrobial action

Atrial Fibrillation and the Prognostic Performance of Biomarkers in Heart Failure

BACKGROUND: Consideration of circulating biomarkers for risk stratification in heart failure (HF) is recommended, but the influence of atrial fibrillation (AF) on prognostic performance of many markers is unclear. We investigated the influence of AF on the prognostic performance of circulating biomarkers in HF. METHODS: N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional-pro-atrial natriuretic peptide, C-type natriuretic peptide (CNP), NT-proCNP, high-sensitivity troponin-T, high-sensitivity troponin-I, mid-regional-propeptide adrenomedullin, co-peptin, growth differentiation factor-15, soluble Suppressor of Tumorigenicitiy (sST2), galectin-3, and procalcitonin plasma concentrations were measured in a prospective, multicenter study of adults with HF. AF was defined as a previous history of AF, and/or presence of AF/flutter on baseline 12-lead electrocardiogram. The primary outcome was the composite of HF-hospitalization or all-cause mortality at 2 years. RESULTS: Among 1099 patients (age 62 +/- 12years, 28% female), 261(24%) patients had AF. Above-median concentrations of all biomarkers were independently associated with increased risk of the primary outcome. Significant interactions with AF were detected for galectin-3 and sST2. In considering NT-proBNP for additive risk stratification, sST2 (adjusted hazard ratio [AHR]1.85, 95%confidence interval [C.I.] 1.17-2.91) and galectin-3 (AHR1.85, 95%C.I. 1.09-2.45) were independently associated with increased primary outcome only in the presence of AF. The prognostic performance of sST2 was also stronger in AF for all-cause mortality (AF: AHR2.82, 95%C.I. 1.26-6.21; non-AF: AHR1.78, 95% C.I. 1.14-2.76 without AF), while galectin-3 predicted HF-hospitalization only in AF (AHR1.64, 95%C.I. 1.03-2.62). CONCLUSIONS: AF modified the prognostic utility of selected guideline-endorsed HF-biomarkers. Application of markers for prognostic purposes in HF requires consideration of the presence or absence of AF

Interference in interacting quantum dots with spin

We study spectral and transport properties of interacting quantum dots with spin. Two particular model systems are investigated: Lateral multilevel and two parallel quantum dots. In both cases different paths through the system can give rise to interference. We demonstrate that this strengthens the multilevel Kondo effect for which a simple two-stage mechanism is proposed. In parallel dots we show under which conditions the peak of an interference-induced orbital Kondo effect can be split.Comment: 8 pages, 8 figure